US10259909B2 - Method for preparing glatiramer acetate - Google Patents

Method for preparing glatiramer acetate Download PDF

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Publication number
US10259909B2
US10259909B2 US15/513,995 US201515513995A US10259909B2 US 10259909 B2 US10259909 B2 US 10259909B2 US 201515513995 A US201515513995 A US 201515513995A US 10259909 B2 US10259909 B2 US 10259909B2
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solution
glatiramer
trifluoroacetyl
stirring
nca
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US20170298180A1 (en
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Huixing YUAN
Guotao LI
Jian Liu
Yaping Ma
Jiancheng Yuan
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Hybio Pharmaceutical Co Ltd
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Hybio Pharmaceutical Co Ltd
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Assigned to Hybio Pharmaceutical Co., Ltd. reassignment Hybio Pharmaceutical Co., Ltd. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LI, Guotao, LIU, JIAN, MA, Yaping, YUAN, Huixing, YUAN, Jiancheng
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids
    • C08G69/04—Preparatory processes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2/00—Peptides of undefined number of amino acids; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids
    • C08G69/36—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids derived from amino acids, polyamines and polycarboxylic acids

Definitions

  • the present invention relates to the field of medicine, more particular, to a method for preparing glatiramer acetate.
  • Autoimmune diseases refer to phenomena that the immune system of an organism treats some of the organism's own tissues as “foreign objects” and attacks them. Normally, such diseases can be alleviated by hindering the response of T cells and B cells of the organism to its own tissues. These early immune reactions are prompted by the binding of antigens to MHC molecules and are performed by T cells.
  • the autoimmune diseases mean that the organism's own tissues and proteins are treated as “self-antigens” and are attacked by the organism's immune system. Taking multiple sclerosis—a disease caused by attack of the immune system on the myelin sheath that isolates and protects nerves—for example, when it progresses to an extent that the myelin sheath is lost, neurons and motor nerves will lose their function.
  • Other diseases such as systemic lupus erythematosus, rheumatoid arthritis, autoimmune hemolytic anemia, also belong to this kind of diseases.
  • Glatiramer acetate also known as copolymer-1, GA
  • GA copolymer-1
  • the molar ratio of the four amino acids in this mixture is about 0.392 to 0.462:0.129 to 0.153:0.300 to 0.374:0.086 to 0.100 (Ala:Glu:Lys:Tyr), and the average molecular weight of the copolymer in the mixture is about 5,000 to 9,000 daltons.
  • Glatiramer acetate is used for treating patients suffering from intermittent recurrent multiple sclerosis, and for reducing the frequency of recurrence.
  • CN101166754B further describes a method, wherein the protected polymer is synthesized, and then it is deprotected with a solution of hydrobromic acid in acetic acid which contains less than 0.5% of free bromine and less than 1000 ppm of metal ions impurities, such that glatiramer acetate is prepared.
  • the present invention relates to a method for preparing highly purified glatiramer acetate, comprising the following steps:
  • the proportion of bromine in the form of elementary substance in the solution of hydrobromic acid in acetic acid ranges from 0.1% to 1%.
  • the solution of hydrobromic acid in acetic acid further contains 0.5 ⁇ 2% (wt %) of phenol, and most preferably, the solution contains 1% (wt %) of phenol.
  • step (1) the volume of 1,4-dioxane is 200 ml, the mass ratio of L-alanine NCA, L-tyrosine NCA, L-glutamic acid- ⁇ -benzyl ester NCA, and L- ⁇ -trifluoroacetyl-lysine NCA is 2.59:1.036:1.974:4.693, and the stirring time is preferably 30 minutes.
  • step (2) the ratio of diethylamine to 1,4-dioxane is 1:6 (v/v), and the ratio of the volume of the water into which the reaction mixture is poured to 1,4-dioxane is 2:1 (v/v), and the drying method of the fully protected glatiramer is preferably vacuum drying after suction filtration.
  • step (3) the ratio of the solution of hydrobromic acid in acetic acid to the fully protected glatiramer is 10:0.74 (w/w), the reaction time is 19 hours, and the ratio of the purified water for quenching to the fully protected glatiramer is 100:3.7 (w/w).
  • step (4) the ratio of trifluoroacetyl glatiramer to the volume of the 1M piperidine aqueous solution is 1:54 (w/v), the stirring time is preferably 24 hours, and the filter membrane used for dialysis is of 2 KDa.
  • the content of bromo-tyrosine is 0.1% to 10%; if a solution of hydrobromic acid in acetic acid containing phenol is used in step (3), the content of bromo-tyrosine in the obtained glatiramer acetate is 0.1% to 0.5%.
  • FIG. 1 is a chromatogram of a glatiramer acetate sample prepared in Example 2.
  • FIG. 2 is a chromatogram of a glatiramer acetate sample prepared in Example 3.
  • FIG. 3 is a chromatogram of a glatiramer acetate sample prepared in Example 4.
  • FIG. 4 is a chromatogram of a glatiramer acetate sample prepared in Example 5.
  • FIG. 5 is a chromatogram of a glatiramer acetate sample prepared in Example 6.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Polymers & Plastics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Epoxy Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Peptides Or Proteins (AREA)
US15/513,995 2014-09-26 2015-11-26 Method for preparing glatiramer acetate Active 2036-07-26 US10259909B2 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201410504852.4 2014-09-26
CN201410504852 2014-09-26
CN201410504852.4A CN104844697B (zh) 2014-09-26 2014-09-26 醋酸格拉替雷的制备方法
PCT/CN2015/095606 WO2016045646A2 (fr) 2014-09-26 2015-11-26 Procédé de préparation d'acétate de glatiramère

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US20170298180A1 US20170298180A1 (en) 2017-10-19
US10259909B2 true US10259909B2 (en) 2019-04-16

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US (1) US10259909B2 (fr)
EP (1) EP3199544B1 (fr)
CN (1) CN104844697B (fr)
EA (1) EA032855B1 (fr)
WO (1) WO2016045646A2 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104844697B (zh) * 2014-09-26 2018-10-23 深圳翰宇药业股份有限公司 醋酸格拉替雷的制备方法
CN107522774B (zh) * 2016-06-22 2021-07-02 深圳翰宇药业股份有限公司 一种醋酸格拉替雷制备过程中哌啶残留量的实时控制方法
CN106279375A (zh) * 2016-11-03 2017-01-04 上海柏际医药科技有限公司 一种醋酸格拉替雷的制备方法
US20190202984A1 (en) * 2018-01-03 2019-07-04 Kinbio Ltd. Process of preparing glatiramer acetate
GB202219045D0 (en) 2022-12-16 2023-02-01 Univ Leeds Innovations Ltd Synthesis of poly(amino acids)

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5800808A (en) 1994-05-24 1998-09-01 Veda Research And Development Co., Ltd. Copolymer-1 improvements in compositions of copolymers
US20070141663A1 (en) * 2005-08-15 2007-06-21 Jinguo Ding Process for the preparation of copolymer-1
US20080118553A1 (en) * 2006-06-12 2008-05-22 Anton Frenkel Tannate salt form of polypeptide mixtures, their preparation and use
US20100036092A1 (en) * 2008-08-07 2010-02-11 Scinopharm Taiwan Ltd. Synthesis of Glatiramer Acetate
WO2010115175A1 (fr) 2009-04-03 2010-10-07 Momenta Pharmaceticals, Inc. Régulation de compositions de copolymères
WO2011022063A1 (fr) 2009-08-20 2011-02-24 Teva Pharmaceutical Industries Ltd. Thérapie à l'acétate de glatiramère à basse fréquence
CN102718963A (zh) 2012-06-19 2012-10-10 深圳翰宇药业股份有限公司 聚合物多肽的制备方法
CN103169670A (zh) 2013-03-22 2013-06-26 深圳翰宇药业股份有限公司 一种醋酸格拉替雷微球及其制备方法
CN103641897A (zh) 2013-11-27 2014-03-19 深圳翰宇药业股份有限公司 一种合成醋酸格拉替雷的方法
CN101166754B (zh) 2004-09-09 2014-04-23 特瓦制药工业有限公司 使用纯化的氢溴酸制备多肽混合物的方法
CN104844697A (zh) 2014-09-26 2015-08-19 深圳翰宇药业股份有限公司 醋酸格拉替雷的制备方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006029411A2 (fr) * 2004-09-09 2006-03-16 Yeda Research And Development Co. Ltd. Melanges de polypeptides, compositions les contenant et leurs procedes de preparation et d'utilisation
WO2012123959A2 (fr) * 2011-02-14 2012-09-20 Usv Limited Copolymère-1, son procédé de préparation et méthodes d'analyse de celui-ci

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5800808A (en) 1994-05-24 1998-09-01 Veda Research And Development Co., Ltd. Copolymer-1 improvements in compositions of copolymers
CN1310673C (zh) 1994-05-24 2007-04-18 耶达研究及发展有限公司 含多肽的多分散混合物的组合物及其药物组合物
CN101166754B (zh) 2004-09-09 2014-04-23 特瓦制药工业有限公司 使用纯化的氢溴酸制备多肽混合物的方法
US20070141663A1 (en) * 2005-08-15 2007-06-21 Jinguo Ding Process for the preparation of copolymer-1
US20080118553A1 (en) * 2006-06-12 2008-05-22 Anton Frenkel Tannate salt form of polypeptide mixtures, their preparation and use
US20100036092A1 (en) * 2008-08-07 2010-02-11 Scinopharm Taiwan Ltd. Synthesis of Glatiramer Acetate
WO2010115175A1 (fr) 2009-04-03 2010-10-07 Momenta Pharmaceticals, Inc. Régulation de compositions de copolymères
WO2011022063A1 (fr) 2009-08-20 2011-02-24 Teva Pharmaceutical Industries Ltd. Thérapie à l'acétate de glatiramère à basse fréquence
CN102718963A (zh) 2012-06-19 2012-10-10 深圳翰宇药业股份有限公司 聚合物多肽的制备方法
CN103169670A (zh) 2013-03-22 2013-06-26 深圳翰宇药业股份有限公司 一种醋酸格拉替雷微球及其制备方法
CN103641897A (zh) 2013-11-27 2014-03-19 深圳翰宇药业股份有限公司 一种合成醋酸格拉替雷的方法
CN104844697A (zh) 2014-09-26 2015-08-19 深圳翰宇药业股份有限公司 醋酸格拉替雷的制备方法

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CN103641897 English Machine translation created Dec. 29, 2018 (Year: 2018). *
CN104844697 Derwent Abstract, Accension No. 2015-61329F, accessed Dec. 29, 2018 (Year: 2018). *
CN104844697 English Machine Translation created Dec. 29, 2018 (Year: 2018). *
Li Rui, et al. Advances in the treatment of multiple sclerosis, Practical Hospital Clinic Magazine. May 31, 2013. pp. 1-5. vol. 10.

Also Published As

Publication number Publication date
WO2016045646A3 (fr) 2016-05-12
US20170298180A1 (en) 2017-10-19
CN104844697A (zh) 2015-08-19
EA201790710A1 (ru) 2017-11-30
CN104844697B (zh) 2018-10-23
WO2016045646A2 (fr) 2016-03-31
EP3199544A2 (fr) 2017-08-02
EP3199544B1 (fr) 2021-11-17
EA032855B1 (ru) 2019-07-31
EP3199544A4 (fr) 2018-06-27

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